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Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

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    Results of 2-year vitamin B treatment on cognitive performance
    Zwaluw, N.L. van der; Dhonukshe-Rutten, R.A.M. ; Wijngaarden, J.P. van; Brouwer, E.M. ; Rest, O. van de; Veld, P.H. in 't; Enneman, A.W. ; Dijk, S.C. van; Ham, A.C. ; Swart, K.M.A. ; Velde, N. van der; Schoor, N.M. van; Cammen, T.J.M. van der; Uitterlinden, A.G. ; Lips, P. ; Kessels, R.P.C. ; Groot, C.P.G.M. de - \ 2014
    Neurology 83 (2014)23. - ISSN 0028-3878 - p. 2158 - 2166.
    folic-acid supplementation - randomized controlled-trial - placebo-controlled trial - alzheimers-disease - elderly-patients - double-blind - homocysteine - metaanalysis - impairment - folate
    Objective: We investigated the effects of 2-year folic acid and vitamin B12 supplementation on cognitive performance in elderly people with elevated homocysteine (Hcy) levels. Methods: This multicenter, double-blind, randomized, placebo-controlled trial included 2,919 elderly participants (65 years and older) with Hcy levels between 12 and 50 µmol/L. Participants received daily either a tablet with 400 µg folic acid and 500 µg vitamin B12 (B-vitamin group) or a placebo tablet. Both tablets contained 15 µg vitamin D3. Data were available for global cognitive functioning assessed by Mini-Mental State Examination (n = 2,556), episodic memory (n = 2,467), attention and working memory (n = 759), information processing speed (n = 731), and executive function (n = 721). Results: Mean age was 74.1 (SD 6.5) years. Hcy concentrations decreased 5.0 (95% confidence interval -5.3 to -4.7) µmol/L in the B-vitamin group and 1.3 (-1.6 to -0.9) µmol/L in the placebo group. Cognitive domain scores did not differ over time between the 2 groups, as determined by analysis of covariance. Mini-Mental State Examination score decreased with 0.1 (-0.2 to 0.0) in the B-vitamin group and 0.3 (-0.4 to -0.2) in the placebo group (p = 0.05), as determined by an independent t test. Conclusions: Two-year folic acid and vitamin B12 supplementation did not beneficially affect performance on 4 cognitive domains in elderly people with elevated Hcy levels. It may slightly slow the rate of decline of global cognition, but the reported small difference may be attributable to chance. Classification of evidence: This study provides Class I evidence that 2-year supplementation with folic acid and vitamin B12 in hyperhomocysteinemic elderly people does not affect cognitive performance.
    A statistical method to base nutrient recommendations on meta-analysis of intake and health-related status biomarkers.
    Voet, H. van der; Boer, W.J. de; Souverein, O.W. ; Doets, E.L. ; Veer, P. van 't - \ 2014
    PLoS ONE 9 (2014)3. - ISSN 1932-6203
    intake values - vitamin-b-12 - population - bioavailability - homocysteine - trials - models - adults - level - nivs
    Nutrient recommendations in use today are often derived from relatively old data of few studies with few individuals. However, for many nutrients, including vitamin B-12, extensive data have now become available from both observational studies and randomized controlled trials, addressing the relation between intake and health-related status biomarkers. The purpose of this article is to provide new methodology for dietary planning based on dose-response data and meta-analysis. The methodology builds on existing work, and is consistent with current methodology and measurement error models for dietary assessment. The detailed purposes of this paper are twofold. Firstly, to define a Population Nutrient Level (PNL) for dietary planning in groups. Secondly, to show how data from different sources can be combined in an extended meta-analysis of intake-status datasets for estimating PNL as well as other nutrient intake values, such as the Average Nutrient Requirement (ANR) and the Individual Nutrient Level (INL). For this, a computational method is presented for comparing a bivariate lognormal distribution to a health criterion value. Procedures to meta-analyse available data in different ways are described. Example calculations on vitamin B-12 requirements were made for four models, assuming different ways of estimating the dose-response relation, and different values of the health criterion. Resulting estimates of ANRs and less so for INLs were found to be sensitive to model assumptions, whereas estimates of PNLs were much less sensitive to these assumptions as they were closer to the average nutrient intake in the available data.
    Bones, brains and B-vitamins : the impact of vitamin B12, folate and homocysteine on bone health and cognitive function in elderly
    Wijngaarden, J.P. van - \ 2013
    Wageningen University. Promotor(en): Lisette de Groot, co-promotor(en): Rosalie Dhonukshe-Rutten. - Wageningen : Wageningen UR - ISBN 9789461737151 - 192
    botontkalking - kenvermogen - ouderen - beenderen - vitamine b12 - foliumzuur - homocysteïne - vitaminetoevoegingen - botbreuken - voedingstoestand - osteoporosis - cognition - elderly - bones - vitamin b12 - folic acid - homocysteine - vitamin supplements - bone fractures - nutritional state


    An elevated homocysteine level has been indicated as a risk factor for cardiovascular disease, cognitive decline, and fractures. Supplementation of vitamin B12 and folic acid in order to normalize homocysteine levels might be of substantial public health importance as this might reduce the risk for several age-related conditions. This thesis focuses on two health outcomes frequently associated with elevated homocysteine levels and low levels of vitamin B12 and folate: osteoporosis and cognitive decline later in life.


    Findings are presented in the context of a model which links dietary intake to biomarkers of nutritional status and subsequently to health outcomes. Two systematic reviews with meta-analyses investigated the current status of knowledge about the association of vitamin B12 intake and status with cognitive function, and the association of homocysteine, vitamin B12 and folate status with bone health. Baseline data of the B-PROOF study were used to assess 1) the association of vitamin B12 intake with status according to four biomarkers (vitamin B12, holotranscobalamin (holoTC), methylmalonic acid (MMA) and homocysteine), 2) the mutual association among these four vitamin B12 biomarkers and 3) the association between homocysteine, vitamin B12 biomarkers, folate and cognitive function. The effect of 2-year daily vitamin B12 (500 μg) and folic acid (400 μg) supplementation on fracture risk was assessed in the B-PROOF study, a large (N=2919) randomized controlled trial in elderly people (aged ≥65 years) with an elevated homocysteine level (≥12.0 µmol/L).


    The systematic review of the literature showed no or inconsistent associations of vitamin B12 intake with cognitive function. Furthermore, serum vitamin B12 was not associated with risk of dementia, global cognition or memory. Studies on MMA and holoTC reported significant associations with risk of dementia, Alzheimer’s disease and global cognition. A meta-analysis showed that serum/plasma vitamin B12 per 50 pmol/L was borderline significantly associated with a lower fracture risk (RR=0.96, 95% CI = 0.92-1.00) and that homocysteine was significantly associated with a higher fracture risk (RR=1.04, 95% CI = 1.02-1.07). Meta-analyses regarding vitamin B12, folate and homocysteine levels and BMD did not show significant associations.

    In the B-PROOF study a doubling of vitamin B12 intake was associated with 9% higher levels of vitamin B12, 15% higher holoTC, 9% lower MMA and 2% lower homocysteine, saturation of biomarkers occurs with dietary intakes of >5 μg B12. Levels of MMA and homocysteine were higher when vitamin B12 levels were below 330 pmol/L and when holoTC levels were below 100 pmol/L, with a steep elevation when levels of vitamin B12 and HoloTC were below 220 and 50 pmol/L respectively. At baseline, levels of vitamin B12 and holoTC were not associated with cognitive function in any cognitive domain. Levels of homocysteine (β= -0.009), folate (β= 0.002), MMA (β= -0.163) and the wellness score – a vitamin B12 biomarker combination score - (β= 0.048) were significantly associated with the domain of episodic memory. Additionally, homocysteine (β= -0.015) and the wellness score (β= 0.103) were significantly associated with the domain information processing speed.

    The B-PROOF intervention did not lower the risk of fracture in the total population (HR=0.84, 95% CI = 0.58-1.22). Per protocol subgroup analysis of elderly aged >80 years, showed a lower risk of fracture in the intervention group (HR=0.28, 95% CI 0.10-0.74). We observed more cancer cases in the intervention group (HR=1.55, 95% CI = 1.04-2.30) compared to the placebo group. We cannot rule out the possibility of accelerated cancer progression as a possible negative side effect.


    Our literature reviews and observational data confirm an association of levels of homocysteine, vitamin B12 and folate with cognitive function and fracture risk in elderly. Supplementation with vitamin B12 and folic acid did not lower the risk of fracture in the total study population. Though positive effects on fracture incidence emerged in elderly aged >80 years, these benefits should be weighed against potential risks.

    Enhancing pterin and para-aminobenzoate content is not sufficient to successfully biofortify potato tubers and Arabidopsis thaliana plants with folate
    Blancquaert, D. ; Storozhenko, S. ; Daele, W. ; Stove, C. ; Visser, R.G.F. ; Lambert, W. ; Straeten, D. van der - \ 2013
    Journal of Experimental Botany 64 (2013)12. - ISSN 0022-0957 - p. 3899 - 3909.
    time quantitative pcr - folic-acid - tomato fruit - gene - expression - transformation - homocysteine - promoter - disease - fortification
    Folates are important cofactors in one-carbon metabolism in all living organisms. Since only plants and micro- organisms are capable of biosynthesizing folates, humans depend entirely on their diet as a folate source. Given the low folate content of several staple crop products, folate deficiency affects regions all over the world. Folate biofortification of staple crops through enhancement of pterin and para-aminobenzoate levels, precursors of the folate biosynthesis pathway, was reported to be successful in tomato and rice. This study shows that the same strategy is not sufficient to enhance folate content in potato tubers and Arabidopsis thaliana plants and concludes that other steps in folate biosynthesis and/or metabolism need to be engineered to result in substantial folate accumulation. The findings provide a plausible explanation why, more than half a decade after the proof of concept in rice and tomato, successful folate biofortification of other food crops through enhancement of para-aminobenzoate and pterin content has not been reported thus far. A better understanding of the folate pathway is required in order to determine an engineering strategy that can be generalized to most staple crops.
    Genetic Variation in Vitamin B-12 Content of Bovine Milk and Its Association with SNP along the Bovine Genome
    Rutten, M.J.M. ; Bouwman, A.C. ; Sprong, R.C. ; Arendonk, J.A.M. van; Visker, M.H.P.W. - \ 2013
    PLoS ONE 8 (2013)4. - ISSN 1932-6203 - 6 p.
    homocysteine - population - lactation - binding - cobalt - folate - cells - cows - fat
    Vitamin B-12 (also called cobalamin) is essential for human health and current intake levels of vitamin B-12 are considered to be too low. Natural enrichment of the vitamin B-12 content in milk, an important dietary source of vitamin B-12, may help to increase vitamin B-12 intake. Natural enrichment of the milk vitamin B-12 content could be achieved through genetic selection, provided there is genetic variation between cows with respect to the vitamin B-12 content in their milk. A substantial amount of genetic variation in vitamin B-12 content was detected among raw milk samples of 544 first-lactation Dutch Holstein Friesian cows. The presence of genetic variation between animals in vitamin B-12 content in milk indicates that the genotype of the cow affects the amount of vitamin B-12 that ends up in her milk and, consequently, that the average milk vitamin B-12 content of the cow population can be increased by genetic selection. A genome-wide association study revealed significant association between 68 SNP and vitamin B-12 content in raw milk of 487 first-lactation Dutch Holstein Friesian cows. This knowledge facilitates genetic selection for milk vitamin B-12 content. It also contributes to the understanding of the biological mechanism responsible for the observed genetic variation in vitamin B-12 content in milk. None of the 68 significantly associated SNP were in or near known candidate genes involved in transport of vitamin B-12 through the gastrointestinal tract, uptake by ileum epithelial cells, export from ileal cells, transport through the blood, uptake from the blood, intracellular processing, or reabsorption by the kidneys. Probably, associations relate to genes involved in alternative pathways of well-studied processes or to genes involved in less well-studied processes such as ruminal production of vitamin B-12 or secretion of vitamin B-12 by the mammary gland
    DNA methylation and cognitive functioning in healthy older adults
    Schiepers, O.J.G. ; Boxtel, M.P.J. van; Groot, R.H.M. ; Jolles, J. ; Kok, F.J. ; Verhoef, P. ; Durga, J. - \ 2012
    The British journal of nutrition 107 (2012)5. - ISSN 0007-1145 - p. 744 - 748.
    physical-activity - common mutation - homocysteine - folate - disorders - reductase - disease
    Long-term supplementation with folic acid may improve cognitive performance in older individuals. The relationship between folate status and cognitive performance might be mediated by changes in methylation capacity, as methylation reactions are important for normal functioning of the brain. Although aberrant DNA methylation has been implicated in neurodevelopmental disorders, the relationship between DNA methylation status and non-pathological cognitive functioning in human subjects has not yet been investigated. The present study investigated the associations between global DNA methylation and key domains of cognitive functioning in healthy older adults. Global DNA methylation, defined as the percentage of methylated cytosine to total cytosine, was measured in leucocytes by liquid chromatography-MS/MS, in 215 men and women, aged 50-70 years, who participated in the Folic Acid and Carotid Intima-Media Thickness (FACIT) study (clinical trial registration number NCT00110604). Cognitive performance was assessed by means of the Visual Verbal Word Learning Task, the Stroop Colour-Word Interference Test, the Concept Shifting Test, the Letter-Digit Substitution Test and the Verbal Fluency Test. Using hierarchical linear regression analyses adjusted for age, sex, level of education, alcohol consumption, smoking status, physical activity, erythrocyte folate concentration and 5,10-methylenetetrahydrofolate reductase 677 C ! T genotype, we found that global DNA methylation was not related to cognitive performance on any of the domains measured. The present study results do not support the hypothesis that global DNA methylation, as measured in leucocytes, might be associated with cognitive functioning in healthy older individuals.
    Transformations of summary statistics as input in meta-analysis for linear dose-response models on a logarithmic scale: a methodology developed within EURRECA
    Souverein, O.W. ; Dullemeijer, C. ; Veer, P. van 't; Voet, Hilko van der - \ 2012
    BMC Medical Research Methodology 12 (2012). - ISSN 1471-2288
    nutritional epidemiology - vitamin-b-12 intake - homocysteine - folate - humans - women - population - error
    Background: To derive micronutrient recommendations in a scientifically sound way, it is important to obtain and analyse all published information on the association between micronutrient intake and biochemical proxies for micronutrient status using a systematic approach. Therefore, it is important to incorporate information from randomized controlled trials as well as observational studies as both of these provide information on the association. However, original research papers present their data in various ways. Methods: This paper presents a methodology to obtain an estimate of the dose-response curve, assuming a bivariate normal linear model on the logarithmic scale, incorporating a range of transformations of the original reported data. Results: The simulation study, conducted to validate the methodology, shows that there is no bias in the transformations. Furthermore, it is shown that when the original studies report the mean and standard deviation or the geometric mean and confidence interval the results are less variable compared to when the median with IQR or range is reported in the original study. Conclusions: The presented methodology with transformations for various reported data provides a valid way to estimate the dose-response curve for micronutrient intake and status using both randomized controlled trials and observational studies.
    A maternal dietary pattern characterised by fish and seafood in association with the risk of congenital heart defects in the offspring
    Obermann-Borst, S.A. ; Vujkovic, M. ; Vries, J.H.M. de; Wildhagen, M.F. ; Looman, C.W. ; Jonge, R. de; Steegers, E.A.P. ; Steegers-Theunissen, R.P.M. - \ 2011
    BJOG : an international journal of obstetrics and gynaecology 118 (2011)10. - ISSN 1470-0328 - p. 1205 - 1215.
    folic-acid supplements - neural-tube defects - nutritional-status - gene-expression - energy-intake - homocysteine - methylation - pregnancy - methionine - period
    Objective To identify maternal dietary patterns related to biomarkers of methylation and to investigate associations between these dietary patterns and the risk of congenital heart defects (CHDs) in the offspring. Design Case–control study. Setting Western part of the Netherlands, 2003–08. Population One hundred and seventy-nine mothers of children with CHD and 231 mothers of children without a congenital malformation. Methods Food intake was obtained by food frequency questionnaires. The reduced rank regression method was used to identify dietary patterns related to the biomarker concentrations of methylation in blood. Main outcome measures Dietary patterns, vitamin B and homocysteine concentrations, biomarkers of methylation (S-adenosylmethionine [SAM] and S-adenosylhomocysteine [SAH]) and the risk of CHD estimated by odds ratios and 95% confidence intervals. Results The one-carbon-poor dietary pattern, comprising a high intake of snacks, sugar-rich products and beverages, was associated with SAH (ß = 0.92, P <0.001). The one-carbon-rich dietary pattern with high fish and seafood intake was associated with SAM (ß = 0.44, P <0.001) and inversely with SAH (ß = -0.08, P <0.001). Strong adherence to this dietary pattern resulted in higher serum (P <0.05) and red blood cell (P <0.01) folate and a reduced risk of CHD in offspring: odds ratio, 0.3 (95% confidence interval, 0.2–0.6). Conclusions The one-carbon-rich dietary pattern, characterised by the high intake of fish and seafood, is associated with a reduced risk of CHD. This finding warrants further investigation in a randomised intervention trial.
    The preconception Mediterranean dietary pattern in couples undergoing in vitro fertilization/intracytoplasmic sperm injection treatment increases the chance of pregnancy
    Vujkovic, M. ; Vries, J.H.M. de; Lindemans, J. ; Macklon, N.S. ; Spek, P.J. van der; Steegers, E.A.P. ; Steegers-Theunissen, R.P.M. - \ 2010
    Fertility and Sterility 94 (2010)6. - ISSN 0015-0282 - p. 2096 - 2101.
    life-style factors - folic-acid - energy-intake - homocysteine - fertility - folate - implantation - performance - population - impact
    Objective: To investigate associations between preconception dietary patterns and IVF/intracytoplasmic sperm injection (ICSI) outcomes validated by biomarkers of the homocysteine pathway. Design: Observational prospective study. Setting: A tertiary referral fertility clinic at the Erasmus University Medical Centre, Rotterdam, The Netherlands. Patient(s): One hundred sixty-one couples undergoing IVF/ICSI treatment. Intervention(s): No interventions other than the Dutch governmental recommendation of folic acid. Main Outcome Measure(s): Dietary patterns, blood and follicular fluid concentrations of folate, vitamin B12, vitamin B6, homocysteine, and fertilization rate, embryo quality, and pregnancy. Result(s): In women, two dietary patterns were identified. The "health conscious-low processed" dietary pattern (variation explained 12.1%) was characterized by high intakes of fruits, vegetables, fish, and whole grains and low intakes of snacks, meats, and mayonnaise, and positively correlated with red blood cell folate (beta=0.07). The "Mediterranean" dietary pattern (variation explained 9.1%), that is, high intakes of vegetable oils, vegetables, fish, and legumes and low intakes of snacks, was positively correlated with red blood cell folate (beta=0.13), and vitamin B6 in blood (beta=0.09) and follicular fluid (beta=0.18). High adherence by the couple to the "Mediterranean" diet increased the probability of pregnancy, odds ratio 1.4 (95% confidence interval 1.0-1.9). Conclusion(s): A preconception "Mediterranean" diet by couples undergoing IVF/ICSI treatment contributes to the success of achieving pregnancy. (Fertil Steril (R) 2010; 94: 2096-101. (C) 2010 by American Society for Reproductive Medicine.)
    The effect of a nutrient dense drink on mental and physical function in institutionalized elderly people
    Manders, M. ; Groot, C.P.G.M. de; Hoefnagels, W.H.L. ; Dhonukshe-Rutten, R.A.M. ; Wouters-Wesseling, W. ; Mulders, A.J.M.J. ; Staveren, W.A. van - \ 2009
    Journal of Nutrition, Health and Aging 13 (2009)9. - ISSN 1279-7707 - p. 760 - 767.
    liquid nutrition supplement - nursing-home residents - alzheimers-disease - cognitive performance - methylmalonic acid - controlled-trial - scale - risk - homocysteine - exercise
    Objectives To determine whether in the current study the supply of a nutrient dense drink has a positive effect on mental and physical function of institutionalized elderly people. Design A 24-week, randomized, double-blind, placebo-controlled, parallel-group, intervention trial. Setting Homes for the elderly and nursing homes in the Netherlands. Participants Institutionalized elderly people older than 60 years, with a BMI = 30 kg/m2, and a Mini-Mental State Examination score of at least 10 points. Intervention In addition to their usual diet the participants (n=176) received either a nutrient dense drink or a placebo drink twice a day during 24 weeks. Measurements The functionality measures included cognitive function, mood, physical performance and the ability to perform activities of daily living. Results In the supplement group a favorable effect of the intervention drink on body weight (1.6 kg difference in change; P =.035), calf circumference (0.9 cm difference in change; P =.048), and blood values (e.g. Hcy decreased from 16.8 to 11.2 µmol/L in the supplement group) was found. In the total group no significant effect was found on functionality outcomes. However, a subgroup of participants with BMI at baseline below 24.4 kg/m2 performed better on the cognitive subscale of Alzheimer’s Disease Assessment Scale (P =.09), and its language sub score (P =.01) after 24 weeks of intervention. Conclusion The results in the total group of this trial suggest that the nutritional supplement used in this study improves nutritional status. Furthermore, the results of this trial suggest that it is effective as treatment for decreasing function in a subgroup of institutionalized elderly people with low BMI.
    Intakes of (n-3) Fatty Acids and Fatty Fish Are Not Associated with Cognitive Performance and 6-Year Cognitive Change in Men Participating in the Veterans Affairs Normative Aging Study
    Rest, O. van de; Spiro, A. ; Krall-Kaye, E. ; Geleijnse, J.M. ; Groot, C.P.G.M. de; Tucker, K.L. - \ 2009
    The Journal of Nutrition 139 (2009)12. - ISSN 0022-3166 - p. 2329 - 2336.
    food frequency questionnaire - erythrocyte-membranes - alzheimers-disease - older-adults - plasma - decline - health - homocysteine - population - risk
    High intake of fish and (n-3) PUFA may protect against age-related cognitive decline. However, results are inconsistent and limited data exist regarding changes in multiple cognitive functions over a longer period of time. In this study, we assessed the association between fatty fish intake as well as (n-3) PUFA intake with cognitive performance and cognitive change over 6 y in 1025 elderly men. Participants were from the Veterans Affairs Normative Aging Study. Cognitive function was assessed with a battery of cognitive tests focusing on factors representing memory/language, speed, and visuospatial/attention. Dietary intakes were assessed with a validated FFQ. We used general linear models to assess cross-sectional associations and mixed models to assess the associations over time. Models were adjusted for age, education, BMI, smoking, diabetes, and intake of alcohol, saturated fat, vitamin C, and vitamin E. The mean age of participating men was 68 y at baseline. Median fish consumption ranged from 0.2 to 4.2 servings/wk across quartiles. Cross-sectional analyses showed no association between fatty fish or (n-3) PUFA intake and cognitive performance. Longitudinal analyses, over 6 y of follow-up, also did not show any significant associations between fatty fish or (n-3) PUFA intake and cognitive change. In this population of elderly men, intake of neither fatty fish nor (n-3) PUFA was associated with cognitive performance
    Role for mitochondrial uncoupling protein-2 (UCP2) in hyperhomocysteinemia and venous thrombosis risk?
    Heil, S.G. ; Vermeulen, S.H. ; Rijt-Pisa, B.J. ; Heijer, M. den; Blom, H.J. - \ 2008
    Clinical Chemistry and Laboratory Medicine 46 (2008)5. - ISSN 1434-6621 - p. 655 - 659.
    homocysteine - translocation - metaanalysis - activation - obesity - disease - trial - cells - mthfr
    Background: Hyperhomocysteinemia has been associated with an increased risk of venous thrombosis, which might be mediated through an oxidative stress dependent mechanism. The function of uncoupling protein-2 (UCP2) is still under debate, but it has been suggested to play a role in reduction of mitochondrial reactive oxygen species. In the present study, we investigated whether the 45 bp deletion/insertion (del/ins) polymorphism in the UCP2 gene is associated with elevated homocysteine levels and whether it might be associated with an increased risk of recurrent venous thrombosis (RVT). Methods: The 45 bp del/ins polymorphism in the UCP2 gene was genotyped by PCR analysis in 161 RVT cases and 386 controls of Caucasian origin in which fasting- and post-load homocysteine levels were previously determined. Statistical analysis was performed to assess whether the UCP2 45 bp del/ins polymorphism was associated with plasma total homocysteine levels and venous thrombosis risk. Results: Post-load homocysteine levels were positively associated with UCP2 45 bp ins/ins genotype (p=0.02). None of the UCP2 45 bp ins/del genotypes were associated with fasting plasma homocysteine levels. The frequency of the UCP2 45 bp ins/ins genotype was 12.4% in RVT cases compared to 8.3% in controls, which resulted in an odds ratio of 1.8 (95% CI 1.0¿3.4). Conclusions: The results of our study show that the common 45 bp del/ins polymorphism in the UCP2 gene is associated with hyperhomocysteinemia, which might increase the risk of venous thrombosis. However, the mechanism is not fully understood and additional studies should be performed to confirm our findings.
    Maternal intake of fat, riboflavin and nicotinamide and the risk of having offspring with congenital heart defects
    Smedts, H.P.M. ; Rakhshandehroo, M. ; Verkleij-Hagoort, A.C. ; Vries, J.H.M. de; Ottenkamp, J. ; Steegers, E.A.P. ; Steegers-Theunissen, R.P.M. - \ 2008
    European Journal of Nutrition 47 (2008)7. - ISSN 1436-6207 - p. 357 - 365.
    neural crest - folic-acid - in-vitro - birth-defects - homocysteine - pregnancy - women - vitamin - disease - obesity
    With the exception of studies on folic acid, little evidence is available concerning other nutrients in the pathogenesis of congenital heart defects (CHDs). Fatty acids play a central role in embryonic development, and the B-vitamins riboflavin and nicotinamide are co-enzymes in lipid metabolism. Aim of the study To investigate associations between the maternal dietary intake of fats, riboflavin and nicotinamide, and CHD risk in the offspring. Methods A case-control family study was conducted in 276 mothers of a child with a CHD comprising of 190 outflow tract defects (OTD) and 86 non-outflow tract defects (non-OTD) and 324 control mothers of a non-malformed child. Mothers filled out general and food frequency questionnaires at 16 months after the index-pregnancy, as a proxy of the habitual food intake in the preconception period. Nutrient intakes (medians) were compared between cases and controls by Mann¿Whitney U test. Odds ratios (OR) for the association between CHDs and nutrient intakes were estimated in a logistic regression model. Results Case mothers, in particular mothers of a child with OTD, had higher dietary intakes of saturated fat, 30.9 vs. 29.8 g/d; P <0.05. Dietary intakes of riboflavin and nicotinamide were lower in mothers of a child with an OTD than in controls (1.32 vs. 1.41 mg/d; P <0.05 and 14.6 vs. 15.1 mg/d; P <0.05, respectively). Energy, unsaturated fat, cholesterol and folate intakes were comparable between the groups. Low dietary intakes of both riboflavin (
    What can we learn from the FACIT trial: A randomized, double blind, controlled trial
    Durga, J. ; Boxtel, M.P.J. van; Schouten, E.G. ; Kok, F.J. ; Jolles, J. ; Katan, M.B. ; Verhoef, P. - \ 2007
    Journal of Nutrition, Health and Aging 11 (2007)4. - ISSN 1279-7707 - p. 320 - 324.
    folic-acid supplementation - cognitive function - memory performance - elderly-patients - homocysteine - dementia - vitamin-b-12 - disease - people - folate
    Effects of Folic Acid Supplementation on Hearing in Older Adults: a Randomized, Controlled Trial
    Durga, J. ; Verhoef, P. ; Anteunis, L.J.C. ; Schouten, E.G. ; Kok, F.J. - \ 2007
    Annals of Internal Medicine 146 (2007)1. - ISSN 0003-4819 - p. 1 - 9.
    cardiovascular risk - vitamin status - rat-brain - homocysteine - folate - population - disease - plasma - serum - hyperhomocysteinemia
    Background: Age-related hearing loss is a common chronic condition of elderly persons. Low folate status has been associated with poor hearing. Objective: To determine whether folic acid supplementation slows age-related hearing loss. Design: Double-blind, randomized, placebo-controlled trial conducted from September 2000 to December 2004. Setting: The Netherlands. Participants: 728 older men and women recruited from municipal and blood bank registries with plasma total homocysteine concentrations 13 mu mol/L or greater serum and vitamin B-12 concentrations 200 pmol/L or greater at screening, and no middle ear dysfunction, unilateral hearing loss, or pathologic ear conditions unrelated to aging. Intervention: Daily oral folic acid (800 mu g) or placebo supplementation for 3 years. Measurements: 3-year change in hearing thresholds, assessed as the average of the pure-tone air conduction thresholds of both ears of the low (0.5-kHz, 1-kHz, and 2-kHz) and high (4-kHz, 6-kHz, and 8-kHz) frequencies. Results: Initial median hearing thresholds were 11.7 dB (interquartile range, 7.5 to 17.5 dB) for low frequencies and 34.2 dB (interquartile range, 22.5 to 50.0 dB) for high frequencies. Sixteen participants (2%) were lost to follow-up. After 3 years, thresholds of the low frequencies increased by 1.0 dB (95% CI, 0.6 to 1.4 dB) in the folic acid group and by 1.7 dB (CI, 1.3 to 2.1 dB) in the placebo group (difference, -0.7 dB [CI, -1.2 to -0.1 dB]; P = 0.020). Folic acid supplementation did not affect the decline in hearing high frequencies. Limitations: The strict criterion for participation on the basis of serum homocysteine concentrations limits extrapolation to the general population. Folic acid fortification of food was prohibited in the Netherlands during the study, so baseline folate levels in participants were about half of those found in the U. S. population. Conclusions: Folic acid supplementation slowed the decline in hearing of the speech frequencies associated with aging in a population from a country without folic acid fortification of food. The effect requires confirmation, especially in populations from countries with folic acid fortification programs.
    Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial
    Durga, J. ; Boxtel, M.P.J. van; Schouten, E.G. ; Kok, F.J. ; Jolles, J. ; Katan, M.B. ; Verhoef, P. - \ 2007
    The Lancet 369 (2007)9557. - ISSN 0140-6736 - p. 208 - 216.
    participants aged 24-81 - normative data - methylenetetrahydrofolate reductase - memory performance - alzheimers-disease - vascular-disease - elderly-patients - homocysteine - education - folate
    Background Low folate and raised homocysteine concentrations in blood are associated with poor cognitive performance in the general population. As part of the FACIT trial to assess the effect of folic acid on markers of atherosclerosis in men and women aged 50-70 years with raised plasma total homocysteine and normal serum vitamin B-12 at screening, we report here the findings for the secondary endpoint: the effect of folic acid supplementation on cognitive performance. Methods Our randomised, double blind, placebo controlled study took place between November, 1999, and December, 2004, in the Netherlands. We randomly assigned 818 participants 800 mu g daily oral folic acid or placebo for 3 years. The effect on cognitive performance was measured as the difference between the two groups in the 3-year change in performance for memory, sensorimotor speed, complex speed, information processing speed, and word fluency. Analysis was by intention-to-treat. This trial is registered with with trial number NCT00110604. Findings Serum folate concentrations increased by 576% (95% CI 539 to 614) and plasma total homocysteine concentrations decreased by 26% (24 to 28) in participants taking folic acid compared with those taking placebo. The 3-year change in memory (difference in Z scores 0.132, 95% CI 0.032 to 0.233), information processing speed (0.087, 0.016 to 0.158) and sensorimotor speed (0.064, -0.001 to 0.129) were significantly better in the folic acid group than in the placebo group. Interpretation Folic acid supplementation for 3 years significantly improved domains of cognitive function that tend to decline with age.
    A dual-isotope-labeling method of studying the bioavailablity of hexaglutamyl folic acid relative to that of monoglutamyl folic acid in humans by using multiple orally administered low doses
    Boonstra, A. ; Verhoef, P. ; West, C.E. ; Rhijn, J.A. van; Breemen, R.B. van; Lasaroms, J.J.P. ; Garbis, S.D. ; Katan, M.B. ; Kok, F.J. - \ 2006
    American Journal of Clinical Nutrition 84 (2006)5. - ISSN 0002-9165 - p. 1128 - 1133.
    performance liquid-chromatography - folate bioavailability - food folate - polyglutamyl folate - urinary-excretion - women - absorption - availability - homocysteine - bioefficacy
    Background: The bioavailability of dietary folate may be hampered by the need of the glutamate moieties to be deconjugated before absorption. Previous studies comparing the bioavailabilities of polyglutamyl and monoglutamyl folic acid had inconsistent results. Objective: The objective was to estimate the bioavailability of polyglutamyl relative to that of monoglutamyl folic acid by using a sensitive stable-isotope approach that allowed for the administration of multiple low doses in humans. Design: Twenty subjects aged 20-50 y ingested 2 capsules daily for 28 d; each capsule contained approximate to 50 nmol [C-13(6)]hexaglutamyl and approximate to 50 nmol [C-13(11)]monoglutamyl folic acid. Amounts of the isotopically labeled compounds in the capsules were verified by various methods. The degrees of isotopic enrichment of plasma 5-methyltetrahydrofolate with C-13(6) and C-13(11) were measured by using liquid chromatography tandem mass spectrometry, and the ratio of C-13(6) to C-13(11) (C-13(6): C-13(11)) in plasma on day 28 was used as a measure of their relative bioavailability. Results: The C-13(11): C-13(6) in plasma 5-methyltetrahydrofolate reached equilibrium on day 4 and was 0.66 (95% CI: 0.58, 0.74) on day 28. The C-13(11): C-13(6) content in the capsules varied between 1.18 and 1.96. After correction for this ratio, the estimated bioavailability of hexaglutamyl relative to that of monoglutamyl folic acid was >= 78%. Conclusion: Multiple dosing of low amounts of labeled folic acid is a sensitive, accurate, and efficient method of measuring the relative bioavailability of folic acid compounds, provided that the administered doses can be reliably assessed.
    Oral cyanocobalamin supplementation in older people with vitamin B12 defiency
    Eussen, S.J.P.M. ; Groot, C.P.G.M. de; Clarke, R.J. ; Schneede, J. ; Ueland, P.M. ; Hoefnagels, W.H.L. ; Staveren, W.A. van - \ 2005
    Archives of Internal Medicine 165 (2005)10. - ISSN 0003-9926 - p. 1167 - 1172.
    normal human-serum - methylmalonic acid - cobalamin deficiency - folate-deficiency - pernicious-anemia - homocysteine - assay - risk
    Background Supplementation with high doses of oral cobalamin is as effective as cobalamin administered by intramuscular injection to correct plasma markers of vitamin B12 deficiency, but the effects of lower oral doses of cobalamin on such markers are uncertain. Methods We conducted a randomized, parallel-group, double-blind, dose-finding trial to determine the lowest oral dose of cyanocobalamin required to normalize biochemical markers of vitamin B12 deficiency in older people with mild vitamin B12 deficiency, defined as a serum vitamin B12 level of 100 to 300 pmol/L (135-406 pg/mL) and a methylmalonic acid level of 0.26 µmol/L or greater. We assessed the effects of daily oral doses of 2.5, 100, 250, 500, and 1000 µg of cyanocobalamin administered for 16 weeks on biochemical markers of vitamin B12 deficiency in 120 people. The main outcome measure was the dose of oral cyanocobalamin that produced 80% to 90% of the estimated maximal reduction in the plasma methylmalonic acid concentration. Results Supplementation with cyanocobalamin in daily oral doses of 2.5, 100, 250, 500, and 1000 µg was associated with mean reductions in plasma methylmalonic acid concentrations of 16%, 16%, 23%, 33%, and 33%, respectively. Daily doses of 647 to 1032 µg of cyanocobalamin were associated with 80% to 90% of the estimated maximum reduction in the plasma methylmalonic acid concentration. Conclusion The lowest dose of oral cyanocobalamin required to normalize mild vitamin B12 deficiency is more than 200 times greater than the recommended dietary allowance, which is approximately 3 µg daily
    Effects of coffee consumption on fasting blood glucose and insulin concentrations: randomized controlled trials in healty volunteers
    Dam, R.M. van; Pasman, W.J. ; Verhoef, P. - \ 2004
    Diabetes Care 27 (2004)12. - ISSN 0149-5992 - p. 2990 - 2992.
    type-2 diabetes-mellitus - caffeine - risk - tolerance - humans - homocysteine - sensitivity - ingestion - exercise - women
    Folate and age-related disease
    Durga, J. - \ 2004
    Wageningen University. Promotor(en): Frans Kok; Evert Schouten, co-promotor(en): P. Verhoef. - [S.I.] : S.n. - ISBN 9789085040910
    foliumzuur - voeding - homocysteïne - hart- en vaatziekten - hart- en vaatstoornissen - ouderen - volwassenen - folic acid - nutrition - homocysteine - cardiovascular diseases - cardiovascular disorders - elderly - adults
    Aging is associated with increased risk of cardiovascular and neurodegenerative disorders and an increase in their risk factors, such as decreased concentrations of folate and increased concentrations of homocysteine. The association of folate and homocysteine with age-related disease and, most importantly, the causality needs to be assessed for effective public health policy. The pathogenic mechanisms, which link these risk factors to age-related diseases may include non-specific disease mechanisms such as inflammation. 

    We investigated the association of folate and homocysteine with cardiovascular disease risk, cognitive performance on a battery of neuropsychological tests and hearing thresholds in middle-aged and elderly men and post-menopausal women using cross-sectional data obtained from the baseline measurements of the FACIT trial. FACIT is an acronym for Folic Acid and Carotid Intima-media Thickness. The FACIT trial investigates the effects of daily folic acid supplementation (0.8 mg/d) for three years on age-related parameters, carotid artery wall thickness and arterial stiffness, cognitive performance and hearing. Furthermore, we investigated whether supplementation with folic acid after one year will lead to a reduction in plasma concentrations of inflammation markers in the final 530 participants of the FACIT trial.

    Low folate status and high concentrations of homocysteine were associated with increased carotid intima-media thickness, a marker of cardiovascular disease risk. However, the relationships were explained to a great part by conventional risk factors (mean difference between first vs. fourth quartile of erythrocyte folate 0.03 mm, 95% confidence interval -0.002 to 0.06 mm). Neither folate nor homocysteine were associated with carotid distension, a measure of arterial stiffness. Decreased concentrations of erythrocyte folate and increased concentrations of homocysteine were independently associated with poor cognitive performance. The cognitive domains with the greatest variability with age, like memory and speed-related functions, were also the domains with the strongest relation with low folate levels. Unexpectedly, folate, not homocysteine, was directly associated with hearing impairment; however, this association was confined to subjects with the 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C allele. Subjects with the MTHFR 677TT genotype had better cognitive performance and hearing levels than subjects with the CC or CT genotype. Finally, inflammation markers did not respond to one-year folic acid supplementation, despite a 25% decrease in homocysteine concentrations.

    Conclusions and implications; mso-ansi-language:EN-US;font-style:normal'>Increased concentrations of folate, independent of its role in homocysteine-lowering, are weakly associated with decreased risk of cardiovascular disease and better cognitive function, but not with hearing acuity. Further research is required to establish whether these relationships are causal and the mechanism responsible for disease. If faced with the decision whether to fortify the national food chain with folic acid, public health policy makers should wait for the large trials to report their findings on the effects of folic acid—alone or in combination with other B vitamins—on cardiovascular disease and dementia.
    Effects of cultivation conditions on folate production by lactic acid bacteria
    Sybesma, W. ; Starrenburg, M. ; Tijsseling, L. ; Hoefnagel, M.H.N. ; Hugenholtz, J. - \ 2003
    Applied and Environmental Microbiology 69 (2003)8. - ISSN 0099-2240 - p. 4542 - 4548.
    gtp cyclohydrolase-i - neural-tube defects - folic-acid - streptococcus-lactis - lactococcus-lactis - enzymatic-synthesis - purification - homocysteine - biosynthesis - strain
    A variety of lactic acid bacteria were screened for their ability to produce folate intracellularly and/or extracellularly. Lactococcus lactis, Streptococcus thermophilus, and Leuconostoc spp. all produced folate, while most Lactobacillus spp., with the exception of Lactobacillus plantarum, were not able to produce folate. Folate production was further investigated in L. lactis as a model organism for metabolic engineering and in S. thermophilus for direct translation to (dairy) applications. For both these two lactic acid bacteria, an inverse relationship was observed between growth rate and folate production. When cultures were grown at inhibitory concentrations of antibiotics or salt or when the bacteria were subjected to low growth rates in chemostat cultures, folate levels in the cultures were increased relative to cell mass and (lactic) acid production. S. thermophilus excreted more folate than L. lactis, presumably as a result of differences in the number of glutamyl residues of the folate produced. In S. thermophilus 5,10-methenyl and 5-formyl tetrahydrofolate were detected as the major folate derivatives, both containing three glutamyl residues, while in L. lactis 5,10-methenyl and 10-formyl tetrahydrofolate were found, both with either four, five, or six glutamyl residues. Excretion of folate was stimulated at lower pH in S. thermophilus, but pH had no effect on folate excretion by L. lactis. Finally, several environmental parameters that influence folate production in these lactic acid bacteria were observed; high external pH increased folate production and the addition of p-aminobenzoic acid stimulated folate production, while high tyrosine concentrations led to decreased folate biosynthesis
    Increased production of folate by metabolic engineering of Lactococcus lactis
    Sybesma, W.F.H. ; Starrenburg, M. ; Kleerebezem, M. ; Mierau, I. ; Vos, W.M. de; Hugenholtz, J. - \ 2003
    Applied and Environmental Microbiology 69 (2003). - ISSN 0099-2240 - p. 3069 - 3076.
    controlled gene-expression - folic-acid - streptococcus-thermophilus - dihydropteroate synthase - subsp cremoris - cloning - bacteria - disease - homocysteine - inhibition
    The dairy starter bacterium Lactococcus lactis is able to synthesize folate and accumulates large amounts of folate, predominantly in the polyglutamyl form. Only small amounts of the produced folate are released in the extracellular medium. Five genes involved in folate biosynthesis were identified in a folate gene cluster in L. lactis MG1363: folA, folB, folKE, folP, and folC. The gene folKE encodes the biprotein 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine pyrophosphokinase and GTP cyclohydrolase I. The overexpression of folKE in L. lactis was found to increase the extracellular folate production almost 10-fold, while the total folate production increased almost 3-fold. The controlled combined overexpression of folKE and folC, encoding polyglutamyl folate synthetase, increased the retention of folate in the cell. The cloning and overexpression of folA, encoding dihydrofolate reductase, decreased the folate production twofold, suggesting a feedback inhibition of reduced folates on folate biosynthesis.
    Bioaccessibility of Folic Acid and (6S)-5-Methyltetrahydrofolate Decreases after the Addiction of Folate-Binding Protein to Yogurt as Studied in a Dynamic In Vitro Gastrointestinal Model
    Arkbåge, K. ; Verwei, M. ; Havenaar, R. ; Witthöft, C. - \ 2003
    The Journal of Nutrition 133 (2003)11. - ISSN 0022-3166 - p. 3678 - 3683.
    neural-tube defects - small-intestine - cows milk - bovine-milk - 5-methyltetrahydrofolate - bioavailability - absorption - homocysteine - transport - diets
    Milk products are only moderate sources of folate. Nevertheless, they are of interest due to their content of folate-binding proteins (FBP), which in some studies have been reported to increase folate bioavailability. The effect of FBP on folate bioavailability has been widely discussed. The aim of this study was to investigate the bioaccessibility of folic acid and (6S)-5- methyltetrahydrofolate (5-CH3-H(4)folate) from fortified yogurt using a dynamic in vitro gastrointestinal model (TIM). In addition, the effect of FBP on folate bioaccessibility and the stability of FBP added to yogurt during gastrointestinal passage were investigated. Folate bioaccessibility was 82% from yogurt fortified with folic acid and 5-CH3-H(4)folate. The addition of FBP to yogurt decreased (P <0.05) folate bioaccessibility. The lowering effect of FBP was more pronounced in yogurt fortified with folic acid (34% folate bioaccessibility) than from yogurt fortified with 5-CH3-H(4)folate (57% folate bioaccessibility). After gastrointestinal passage, 17% of the FBP in yogurt fortified with 5-CH3-H(4)folate and 34% of the FBP in yogurt fortified with folic acid were recovered. No difference in folate bioaccessibility was found between folate-fortified yogurt and folate-fortified pasteurized milk (P = 0.10), whereas the lowering effect of FBP was (P <0.05) greater in yogurt compared with pasteurized milk. In conclusion, based on the high bioaccessibility of folic acid and 5-CH3-H(4)folate, yogurt without active FBP can be considered to be an appropriate food matrix for folate fortification.
    Vitamin B12 status is associated to bone mineral content and bone mineral density in frail elderly women, but not in men
    Dhonukshe-Rutten, R.A.M. ; Lips, M. ; Jong, N. ; Chin A Paw, M.J.M. ; Hiddink, G.J. ; Dusseldorp, M. van; Groot, C.P.G.M. de; Staveren, W.A. van - \ 2003
    The Journal of Nutrition 133 (2003)3. - ISSN 0022-3166 - p. 801 - 807.
    physical-activity scale - methylmalonic acid - osteoporosis - determinants - nutrition - exercise - mass - absorptiometry - homocysteine - vegetarian
    Subclinical vitamin B-12 deficiency is common in the elderly. Encouraged by early indications, we investigated the plasma vitamin B-12 status in association with bone mineral content (BMC) and bone mineral density (BMD) in frail elderly people. Data of 194 free-living Dutch frail elderly (143 women and 51 men) were available. BMC and BMD were measured by dual energy X-ray analysis. Biochemical analyses were performed on plasma or serum including vitamin B-12, methylmalonic acid, homocysteine, 25-hydroxy vitamin D and parathyroid hormone. Women had higher plasma vitamin B-12 (288 and 238 pmol/L, respectively) and lower plasma homocysteine levels (15.8 and 21.3 mumol/L, respectively) than men. Of the total explained variance of BMC and BMD in women (46 and 22%, respectively), 1.3-3.1% was explained by plasma vitamin B-12, in addition to weight and height or energy intake. In men, the variance of BMC and BMD was explained by weight, smoking and/or height (total R-2 was 53 and 25%, respectively), but not by plasma vitamin B-12. Osteoporosis occurred more often among women whose vitamin B-12 status was considered marginal or deficient than in women with a normal status, i.e., the prevalence odds ratios (after adjustment for weight, age and calcium intake) (95% confidence intervals) were 4.5 (0.8;24.8) and 6.9 (1.2;39.4), respectively. These results suggest that vitamin B-12 status is associated with bone health in elderly women. Future studies on bone health should take into account a possible role of vitamin B-12 status in different populations.
    Homocysteine and coronary heart disease : the role of polymorphic genes and hemostasis
    Klerk, M. - \ 2002
    Wageningen University. Promotor(en): F.J. Kok; E.G. Schouten; P. Verhoef. - S.l. : S.n. - ISBN 9789058087737 - 145
    hartziekten - homocysteïne - genetische polymorfie - hemostase - heart diseases - homocysteine - genetic polymorphism - haemostasis

    Background Homocysteine is a sulfur-containing amino acid formed during catabolism of the essential amino acid methionine. Defects in genes encoding enzymes or sub-optimal intake of B-vitamins (e.g. folate) involved in homocysteine metabolism can lead to cellular accumulation of homocysteine resulting in elevated plasma levels. Numerous epidemiological studies have shown a positive association between elevated homocysteine levels and cardiovascular disease (CVD) risk. However, whether elevated homocysteine is a causal risk factor of CVD is still under debate. In addition, the pathogenic mechanism through which homocysteine would increase CVD risk is still unclear, but one of the proposed mechanisms is that homocysteine would impair hemostasis .

    Methods The epidemiological studies described in this thesis explored the evidence with respect to a causal role of homocysteine in the occurrence of coronary heart disease (CHD) by investigating the association of polymorphic genes with risk of CHD. Two placebo-controlled intervention studies on homocysteine lowering in humans investigated the role of hemostasis as a potential mechanism.

    Results In a meta-analysis we showed that homozygosity for the 677C>T mutation in the gene encoding methylenetetrahydrofolate reductase (MTHFR), an enzyme involved in homocysteine remethylation, was associated with a higher risk of CHD, however only when folate status was low. This might explain why the mutation was associated with increased CHD risk in Europe, but not in North America, where folate intake is higher because of widespread use of vitamin supplements and folate fortification. In a case-control study, we observed an increased risk of CHD for individuals who were homozygous for the 2756A>G mutation in the gene encoding methionine synthase (MS), another enzyme involved in homocysteine remethylation. However, this could not be confirmed by the majority of other published case-control studies. In two trials, B-vitamin or folic acid supplementation had no clear beneficial effect on markers of hemostasis, despite a marked reduction in homocysteine concentrations was observed.

    Conclusions The result of our meta-analysis on the MTHFR 677C>T polymorphism and CHD supports the hypothesis that impaired folate metabolism, leading to high homocysteine concentrations, is causally related to CHD risk. The meta-analysis could not reveal whether it is elevated homocysteine, low folate or impaired methylation that is the true cause of CHD. However, our results suggest that increasing population mean levels of folate would reduce the incidence of CHD. This could be achieved by improving the bioavailability of folate from foods and additional food fortification with folic acid. Provided the folate status is adequate, there is little additional value of screening for MTHFR 677C>T genotype. Homocysteine-lowering through B-vitamin supplementation does not seem to affect hemostasis in healthy volunteers. More research is needed to unravel the pathogenic mechanism.

    Bioavailability of flavonoids and cinnamic acids and their effect on plasma homosysteine in humans
    Olthof, M.R. - \ 2001
    Wageningen University. Promotor(en): M.B. Katan; P.C.H. Hollman. - S.l. : S.n. - ISBN 9789058084170 - 135
    flavonoïden - kaneelzuur - homocysteïne - bloedplasma - biologische beschikbaarheid - mens - quercetine - theaflavine - chlorogeenzuur - hart- en vaatziekten - flavonoids - cinnamic acid - homocysteine - blood plasma - bioavailability - man - quercetin - theaflavine - chlorogenic acid - cardiovascular diseases

    Dietary antioxidants might prevent oxidative damage to tissues and therefore protect against cardiovascular disease and cancer. Dietary phenols are strong antioxidants in vitro but their role in vivo is uncertain. Furthermore, there are only limited data on their bioavailability in humans. The aim of this thesis was to investigate whether bioavailability data on flavonoids and cinnamic acids support the hypothesis that they can affect health in humans . Because the group of phenols in foods is huge, we focussed our research on major phenols in foods; the flavonol quercetin, black tea phenols and chlorogenic acid (5-caffeoylquinic acid). We studied their bioavailability and effect on plasma homocysteine in humans, a potential risk factor for cardiovascular disease.

    The bioavailability of quercetin and chlorogenic acid depends upon their conjugated moieties. Hollman et al. found that the bioavailability of quercetin-3-rutinoside, a major flavonol in tea, was only 20% of that of quercetin-4'-glucoside. We found that transformation of quercetin-3-rutinoside into quercetin-3-glucoside will improve its bioavailability because the 3-glucoside had the same high bioavailability as the 4'-glucoside. Caffeic acid is a major phenol in coffee, but it is present as a conjugate with quinic acid, called chlorogenic acid. We found that the conjugation of caffeic acid with quinic acid hinders absorption in humans: absorption of chlorogenic acid was only 30% of that of its caffeic acid moiety.

    Furthermore, we found that chlorogenic acid, black tea solids and quercetin-3-rutinoside are extensively metabolized in the human body, mainly before they reach the circulation. Their metabolites have no, or less, antioxidant activity in vitro than their parent phenols. Therefore the role of dietary phenols as antioxidants in vivo might be less important than suggested by their in vitro antioxidant activity.

    Coffee consumption increases plasma homocysteine, a potential risk factor for cardiovascular disease. Chlorogenic acid from coffee is partly responsible for the homocysteine-raising effect of coffee, because we found that it increased plasma homocysteine. Black tea solids also raised plasma homocysteine, whereas quercetin-3-rutinoside did not. Furthermore, we found that glycination of metabolites of phenols in the body is not involved in the homocysteine-raising effect of phenols.

    In conclusion, chlorogenic acid, tea phenols and quercetin are available in the human body, but their effects on health are uncertain. Further research on bioavailability and health effects of dietary phenols is needed.

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